1. Field of the Invention
The present invention relates to a pharmaceutical composition comprising nicotinic acid adenine dinucleotide phosphate (NAAPD) or a derivative thereof useful for the treatment or prevention of type-2 diabetes (non-insulin-dependent diabetes mellitus; NIDDM)) or medical symptoms, which reduce the glucose threshold for insulin secretion, and to a method for treating type-2 diabetes using the compound. More specifically, the present invention relates to the use of nicotinic acid adenine dinucleotide phosphate or a derivative thereof as an agent for treating type-2 diabetes, because nicotinic acid adenine dinucleotide phosphate or a derivative thereof improves the insulin secretion ability of pancreatic β-islet cells isolated from normal mice (C57BL/6) and, when administered intraperioneally to type-2 diabetic mice, has excellent effects of lowering blood glucose levels and stimulating insulin secretion.
2. Description of the Prior Art
An increase in calcium concentration in beta-cells is attributable to extracellular calcium entry and rapid calcium release from extracellular calcium stores into the cytoplasm and induces insulin secretion (Wollheim C B et al., J Biol Chem 250:1354-1360, 1975., Rojas E. et al., Endocrinology 134:1771-1781, 1994., Cancela J M et al., Diabetes Suppl 3:S349-S357, 2002., Rutter G A., Mol Aspects Med 22:247-284, 2001).
An elevation in blood glucose levels stimulates insulin secretion through a specialized pathway that requires mitochondrial ATP synthesis, which leads to the closure of ATP-sensitive K+ channels, the depolarization of cells and the entry of extracellular cells (Hinke S A et al., J Physiol 558:369-380, 2004). Furthermore, a glucose-mediated elevation in calcium concentration is achieved through the following two calcium releasing receptors in the endoplasmic reticulum: IP3 receptor for inositol 1,4,5-trisphosphate (IP3) stimulated by IP3/phospholipase C activation, and ryanodine receptor activated by cyclic ADP-ribose (cADPR) (Ammala C et al., Nature 353:849-852, 1991, Okamoto H., Mol Cell Biochem 193:115-118, 1999). Recent studies have indicated that cADPR also induces the entry of extracellular calcium (Rah S Y et al., J Biol Chem 280:2888-2895, 2005; Togashi K. et al., EMBO J. 25:1804-1815, 2006). It was reported that an additional pathway for the intracellular calcium release channel into the cytoplasm is the nicotinic acid adenine dinucleotide phosphate-sensitive receptor channel present in acidic lysosome-related granules (Churchill G C et al., J Biol Chem 275:38687-38692, 2000). Such cADPR and NAADP are synthesized by CD38 (Aarhus R et al., J Biol Chem 270:30327-30333, 1995; Chini E N et al., Biochem J 362:125-130, 2002). It was reported that glucose-stimulated calcium mobilization and insulin secretion are elevated by CD38 overexpression (Kato I et al., J Biol Chem 270:30045-30050, 1995) and reduced by CD38 knockout (Kato I et al., J Biol Chem 274:1869-1872, 1999). Low levels of CD38 expression have been observed in diabetic β-cells isolated from an ob/ob mouse model and in RINm5F insulinoma cells with poor glucose-stimulated insulin production/release (Takasawa S et al., J Biol Chem 273:2497-2500, 1998). A recent study has indicated that NAADP initiates and propagates calcium signals in response to insulin and is involved in insulin synthesis (Johnson J D et al., Proc Natl Acad Sci USA 99: 14566-14571, 2002).
Along the same lines, NAADP-sensitive calcium store-controlled calcium signaling and the production of NAADP by glucose stimulus in β-cells have also been demonstrated (Masgrau Ret al., Curr Biol 13:247-251, 2003; Yamasaki M et al., J Biol Chem 279:7234-7240, 2004).
Glucagon-like peptide-1 (GLP-1), a peptide hormone released from gut L-cells, is a physiologically important potentiator of glucose-induced insulin secretion (Kieffer T J and Habener J F: Endocr Rev 20:876-913, 1999; Holz G G and Chepurny O G, Sci STKE 2005(268):pe2, 2005). The peptide GLP-1 elevates intracellular cAMP concentrations and activates protein kinase A (PKA) and cAMP-regulated guanine nucleotide exchange factor II (cAMP-GEFII or Epac) (Delmeire D et al., Diabetologia 46:1383-1393, 2003; Kang G et al., J Physiol 566:173-188, 2005). Although these cAMP-binding proteins have been shown to play a role in GLP-1-mediated transient and sustained increase of calcium (Holz G G, Horm Metab Res 36:787-794, 2004), it remains to be clarified whether the increase of calcium is mediated through direct activation of calcium channels. In addition, the role of NAADP in calcium migration by PKA and Epac is not known, and the use of NAADP as an agent for treating diabetes is also not known.
In addition, Johnson J D et al. reported that nicotinic acid adenine dinucleotide phosphate increases insulin expression in beta-cells without increasing calcium, but does not increase insulin secretion (Johnson J D and Misler S., PNAS (2002) 99(22), 14566-14571).